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. 2026 Jan 6;32(1):169-178.
doi: 10.1158/1078-0432.CCR-25-3033.

Clinical and Genomic Factors Associated with Elacestrant Outcomes in ESR1-Mutant Metastatic Breast Cancer

Maxwell R Lloyd  1 , Caroline M Weipert  2 , Azka Ali  3 , Sheila R Solomon  2 , Jayati Saha  2 , Marla D Lipsyc-Sharf  4 , Erika P Hamilton  5 , Kevin Kalinsky  6 , Adam M Brufsky  7 , Aditya Bardia  4 , Nicole Zhang  2 , Seth A Wander  8
Affiliations

Clinical and Genomic Factors Associated with Elacestrant Outcomes in ESR1-Mutant Metastatic Breast Cancer

Maxwell R Lloyd et al. Clin Cancer Res. .

Abstract

Purpose: ESR1 mutations mediate resistance to antiestrogen therapy in hormone receptor-positive metastatic breast cancer (MBC). Elacestrant, an oral selective estrogen receptor degrader, improves progression-free survival over standard endocrine therapy in ESR1-mutant MBC. We assessed real-world elacestrant use and clinical-genomic factors associated with outcomes.

Experimental design: This study used the GuardantINFORM database, linking >42,000 real-world breast cancer cases with sequencing and claims data. We included patients with activating ESR1 mutations detected <6 months before elacestrant initiation (January 2023-March 2024). Outcomes of time-to-treatment-discontinuation, time-to-next-treatment (TTNT), and overall survival were estimated with Kaplan-Meier and Cox regression analysis, adjusting for clinical variables.

Results: We identified 756 patients (76% with prior cyclin-dependent kinase-4/6 inhibitor and 38% with prior chemotherapy exposure), and 742 (98.2%) were evaluable for outcomes. The median TTNT was 6.4 months, and the time-to-treatment-discontinuation was 4.6 months. In those with ≤1 prior lines of metastatic therapy, the TTNT was 8.8 months, compared with 6.0 months in the third-line setting. Prior fulvestrant exposure trended toward shorter treatment duration (hazard ratio, 1.19; 95% confidence interval, 0.91-1.56). Higher ESR1 polyclonality (≥4 alterations; 11% of patients) correlated with a shorter TTNT of 5.2 months (hazard ratio, 1.44; 95% confidence interval, 1.01-2.06), but efficacy was consistent across ESR1 alleles (e.g., Y537S and D538G). Disease with dual ESR1 and PI3K pathway mutations (PIK3CA, AKT1, and PTEN) had a median TTNT of 5.2 months.

Conclusions: In ESR1-mutant MBC, elacestrant treatment durations support the routine use of elacestrant monotherapy in appropriately selected patients. For patients with concurrent ESR1 and PI3K pathway mutations, single-agent activity was comparable with outcomes observed in phase III studies. See related article by Rugo et al., p. 179.

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Conflict of interest statement

C.M. Weipert reports employment with and stock ownership in Guardant Health, Inc. A. Ali reports other support from Guardant Health, Stemline Therapeutics, Pfizer, AstraZeneca, and TerSera Therapeutics outside the submitted work. S.R. Solomon reports employment with and stock ownership in Guardant Health, Inc. J. Saha reports employment with and stock ownership in Guardant Health, Inc. M.D. Lipsyc-Sharf reports personal fees from Exact Sciences, Guardant Health, Eli Lilly, Novartis, Stemline Therapeutics, and TerSera Therapeutics outside the submitted work. E.P. Hamilton reports grants from Stemline Therapeutics during the conduct of the study, as well as grants from AbbVie, Accutar Biotechnology, Artios, AtlasMedx, BeiGene, Bicycle Therapeutics, Biohaven Pharmaceuticals, BioNTech, Compugen, Cullinan, Dantari, Day One Biopharmaceuticals, Duality Biologics, Ellipses Pharma, Elucida Oncology, Exelixis, FujiFilm, Genmab, H3 Biomedicine, Iambic Therapeutics, Immunogen, Inspirna, InventisBio, Jacobio, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, MabSpace Biosciences, Mabwell Bioscience, Maregno Therapeutics, MediLink Therapeutics, Merck, Olema, Orinove, Orum Therapeutics, Pionyr Immunotherapeutics, Prelude Therapeutics, Profound Bio, Regeneron, Relay Therapeutics, Rgenix, Seagen, Shattuck Labs, Simcha Therapeutics, Sutro, Systimmune, Taiho, TheRas, Treadwell Therapeutics, Verastem, Xadcera Biopharmaceutical, and Zymeworks; grants and other support from Arvinas, AstraZeneca, Daiichi Sankyo, Gilead Sciences, Jazz Pharmaceuticals, Lilly, Mersana, Novartis, Pfizer, Roche/Genentech, and Stemline Therapeutics; and other support from BeOne Medicines, Boehringer Ingelheim, Boundless Bio, Bristol Myers Squibb, Circle Pharma, Halda Therapeutics, Incyclix Bio, IQVIA, Janssen, Jefferies, Johnson and Johnson, Precede Biosciences, Pyxis Oncology, Samsung Bioepis, Shorla Pharma, and Tempus Labs outside the submitted work. K. Kalinsky reports personal fees from Genentech/Roche, Gilead, Seattle Genetics, AstraZeneca, Daiichi Sankyo, Puma Biotechnology, Mersana, Menarini Silicon Biosystems, Myovant Sciences, Merck, Eli Lilly, Pfizer, Novartis, Mersana, ProteinQure, bioTheranostics, Regor Therapeutics, and Relay Therapeutics outside the submitted work, as well as from EQRX (prior employee) and ADC Therapeutics. A.M. Brufsky reports personal fees from Menarini and Stemline Therapeutics during the conduct of the study, as well as personal fees from AstraZeneca, Pfizer, Novartis, Lilly, Roche, Puma, Gilead, Daiichi Sankyo, Celcuity, Bria-Cell, and Merck outside the submitted work. A. Bardia reports grants and personal fees from Pfizer, Novartis, Merck, Genentech, AstraZeneca/Daiichi, Alyssum, Menarini, Gilead, and Eli Lilly during the conduct of the study. N. Zhang reports employment with and stock ownership in Guardant Health, Inc. S.A. Wander reports personal fees from Halda Therapeutics, Gilead, Foundation Medicine, Veracyte, Hologic, Biovica, Novartis, and AstraZeneca; personal fees and other support from Celcuity, Eli Lilly, Pfizer/Arvinas, Puma Biotechnology, Genentech, Regor Therapeutics, and Stemline/Menarini; and other support from Sermonix, Phoenix Molecular Designs, and Nuvation Bio outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Clinical outcomes in patients treated with elacestrant. A depicts the TTNT since elacestrant initiation in this cohort of patients with MBC and ESR1 mutation detected within 6 months prior to therapy start. B displays the TTD in this cohort, and C displays the OS. Vertical hash marks denote a censored patient event. CL, confidence limit.
Figure 2.
Figure 2.
Patient outcomes on elacestrant by prior lines of therapy. TTNT (A), TTD (B), and OS (C) on elacestrant are depicted comparing differences in outcomes by the number of prior lines of metastatic therapy. Patients who received elacestrant after one or fewer prior lines are displayed in blue, after two prior lines are displayed in red, and after three or more prior lines are displayed in green. Adjusted HR and corresponding 95% CI are displayed comparing patients with two prior lines and three or more prior lines with those with one or fewer prior lines of metastatic therapy before elacestrant initiation. Vertical hash marks denote a censored patient event. CL, confidence limit; pts, patients.
Figure 3.
Figure 3.
Elacestrant therapy duration and OS by prior fulvestrant exposure. Depicted are clinical outcomes on elacestrant therapy comparing patients with versus those without previous treatment with fulvestrant. Patients treated with fulvestrant before elacestrant are displayed in red, and those without prior fulvestrant are displayed in blue. A depicts the TTNT, B depicts the TTD, and C depicts the OS. The adjusted HR and corresponding 95% CI comparing the two groups are displayed. Vertical hash marks denote a censored patient event. CL, confidence limit.
Figure 4.
Figure 4.
Differences in elacestrant efficacy in patients with polyclonal versus single ESR1-mutant tumors. Among this cohort of patients with a baseline ESR1 mutation detected within 6 months of elacestrant start, clinical outcomes in patients with two, three, or four or more detectable ESR1 alterations were compared with patients with one ESR1 mutation. A depicts the TTNT on elacestrant, B depicts the TTD, and C depicts the OS comparing those with two ESR1 mutations in red, three in green, and four or more in brown against patients with a single ESR1 mutation in blue. The adjusted HR and corresponding 95% CI are displayed. Vertical hash marks denote a censored patient event. ESR1 alt denotes ESR1 alteration. alt, alteration; CL, confidence limit; pts, patients.
Figure 5.
Figure 5.
PI3K pathway alterations are associated with differences in clinical outcomes on elacestrant. Patients with PI3K pathway–altered tumors were defined by the presence of an oncogenic PIK3CA, AKT1, and/or PTEN alteration detected within 6 months prior to elacestrant exposure. Clinical outcomes in patients with PI3K pathway–altered disease (in red) were compared with those without a PI3K pathway alteration (in blue) via the TTNT (depicted in A), TTD (depicted in B), and OS (depicted in C). The adjusted HR and corresponding 95% CI are displayed. Vertical hash marks denote a censored patient event CL, confidence limit.
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